The council for International Organizations of Medical Sciences (CIOMS) acknowledges
the very substantial contribution, financial and technical, of the World Health
Organization Global Programme on AIDS to the preparation of International
Ethical Guidelines for Research Involving Human Subjects. The two other
Special Programmes of the World Health Organization  on Research, Development
and Research Training in Human Reproduction, and for Research and Training in
Tropical Diseases  also gave valuable support. CIOMS acknowledges also with
much appreciation the financial contribution of the Sandoz Foundation in the
United States of America and the International Development Research Centre of
Canada.

Of the many individuals who contributed to the preparation of the Guidelines,
the following merit special acknowledgement: Professor Robert J. Levine who
was Co-Chairman of the CIOMS Steering Committee and the Conference on Ethics
and Research on Human Subjects  International Guidelines, and provided invaluable
assistance from the inception of the project, particularly in the preparation
of several drafts and the final text of the Guidelines; Professor John H. Bryant
who co-chaired the Conference and the Steering Committee, and whose wise counsel
was available throughout; Professor Bernard M. Dickens and Mr Richard Kelly
who prepared the first draft of the Guidelines; Professor Lawrence O. Gostin,
for his part in preparing An Annotated Guide to Ethical Review, which was used
in the preparation of the Guidelines; and Professors Mohamed Abdussalam, Wendy
Mariner and Benjamin O. Osuntokun, Mr Frank Gutteridge, Mr Sev Fluss and Dr
Michel Thuriaux, who contributed actively from the beginning. Special thanks
go to Dr James Gallagher for his contribution to the final drafting and editing
of the Guidelines, and to Mrs Kathryn Chalaby-Amsler for her invaluable secretarial
assistance.

BACKGROUND NOTE

Advances in biomedical science and technology, and their application in the
practice of medicine, are provoking some anxiety among the public and confronting
society with new ethical problems. Society is expressing concern about what
it fears would be abuses in scientific investigation and biomedical technology.
This is understandable in view of the methodology of biomedical experimental
research. Investigation begins with the construction of hypotheses and these
are then tested in laboratories and with experimental animals. For the findings
to be clinically useful, experiments must be performed on human subjects, and,
even though carefully designed, such research entails some risk to the subjects.
This risk is justified not by any personal benefit to the researcher or the
research institution, but rather by its benefit to the human subjects involved,
and its potential contribution to human knowledge, to the relief of suffering
or to the prolongation of life.

Society devises measures to protect against possible abuses. The first international
code of ethics for research involving human subjects  the Nuremberg Code 
was a response to the atrocities committed by Nazi research physicians, revealed
at the Nuremberg War Crimes Trials. Thus it was to prevent any repetition by
physicians of such attacks on the rights and welfare of human beings that human-research
ethics came into being. The Nuremberg Code, issued in 1947, laid down the standards
for carrying out human experimentation, emphasizing the subject's voluntary
consent. In 1964 the World Medical Association took an important step further
to reassure society: it adopted the Declaration of Helsinki, most recently revised
in 1989, which lays down ethical guidelines for research involving human subjects.
In 1966 the United Nations General Assembly adopted the International Covenant
on Civil and Political Rights, which entered into force in 1976, and which states
(Article 7): "No one shall be subjected to torture or to cruel, inhuman or
degrading treatment or punishment. In particular, no one shall be subjected
without his free consent to medical or scientific experimentation ". It
is through this statement that society expresses the fundamental, human value
that is held to govern all research involving human subjects  the protection
of the rights and welfare of all human subjects of scientific experimentation.

In the late 1970s, in view of the special circumstances of developing countries
in regard to the applicability of the Nuremberg Code and the Declaration of
Helsinki, the Council for International Organizations of Medical Sciences (CIOMS)
and the World Health Organization (WHO) undertook a further examination of these
matters, and in 1982 issued Proposed International Guidelines for Biomedical
Research Involving Human Subjects. The purpose of the Proposed Guidelines
was to indicate how the ethical principles that should guide the conduct
of biomedical research involving human subjects, as set forth in the Declaration
of Helsinki, could be effectively applied, particularly in developing

countries, given their socioeconomic circumstances, laws and regulations, and
executive and administrative arrangements.

Proposed Guidelines received extensive distribution and, according to
a later survey, went into use widely throughout the world, provide valuable
ethical guidance in biomedical research involving human subjects. Survey respondents
and other users indicated also that the guidelines should be reviewed with particular
reference to the ethical issues raised by large-scale trials of vaccines and
drugs, transnational research, and experimentation involving vulnerable population
groups. A particular indication for their revision was the prospect of field
trials of vaccines and drugs to control AIDS. Moreover, in recent years, many
people, in developed and developing countries alike, have begun to see the beneficial
and not only the threatening aspects of research involving human subjects; indeed
such research, particularly related to innovative therapy trials, is now actively
sought by potential beneficiaries for some, participation in research is the
only way they can gain access to valuable new treatment or even general medical
care; for others, it is the means by which scientists will discover new knowledge
that may lead to the prevention or treatment or even elimination of certain
categories of disease and disability.

In these circumstances CIOMS undertook, in collaboration with WHO, the revision
of the guidelines, setting up a steering committee to guide the process. The
Steering Committee decided that in the revision special attention should be
paid to epidemiological studies, owing to the importance of epidemiology, particularly
for public health, and to the need for international guidelines for ethical
review of such studies. In the event, it was determined that this need would
be best met by a separate publication, and the result was the issuing by CIOMS
in 1991 of International Guidelines for Ethical Review of Epidemiological
Studies. The preparation of the epidemio1ogical guidelines contributed materially
to the revision of the 1982 guidelines.

After extensive consultation the first draft of the revised guidelines was
prepared by a group of consultants, reviewed and amended by the Steering Committee,
and presented to the CIOMS Conference on Ethics and Research on Human Subjects
 International Guidelines, held in Geneva in February 1992. At the conference
it was examined and discussed by some 150 participants from both developed and
developing countries, including representatives of ministries of health and
medical and other health-related disciplines, health policy-makers, ethicists,
philosophers and lawyers.

The draft guidelines were revised to reflect the consensus of the conference,
but with due regard to minority points of view. The revised draft was then sent
for comment to the conference participants, international associations, and
to medical research councils and other interested bodies and institutions in
both developed and developing countries. The final text duly reflects the comments
received. It has been endorsed by the WHO Global Advisory Committee on Health
Research and the Executive Committee of CIOMS, which have recommended its publication
and wide distribution.

The text consists of a statement of general ethical principles, a preamable
and 15 guidelines, with an introduction, and a brief account of earlier ethical
declaration and guidelines. Bach guideline is followed by a commentary.

The guidelines reflect the paramount ethical concern for vigilance in protecting
the rights and welfare of research subjects and of vulnerable individuals or
groups being considered as prospective subjects. Like the original (1982) guidelines,
the revised guidelines are designed to be of use, particularly to developing
countries, in defining national policies on the ethics of biomedical research,
applying ethical standards in local circumstances, and establishing or redefining
adequate mechanisms for ethical review of research involving human subjects.

Certain areas of research do not receive special mention in these guidelines;
they include human genetic research, embryo and fetal research, and fetal tissue
research. These represent research areas in rapid evolution and in various respects
controversial. The Steering Committee considered that since there is not universal
agreement on all the ethical issues raised by these research areas it would
be premature to try to cover them in the present guidelines.

The mere formulation of ethical guidelines for biomedical research involving
human subjects will hardly resolve all the moral doubts that can arise in association
with such research, but the guidelines can at least draw the attention of investigators,
sponsors and ethical review committees to the need to consider carefully the
ethical implications of research protocols and the conduct of research, and
thus conduce to high scientific and ethical standards of research.

Comments on the Guidelines are welcome, and will be taken into account in future
revisions. They should be addressed to:

As a result of collaboration on research ethics between the World Health Organization
(WHO) and the Council for International Organizations of Medical Sciences (CIOMS),
CIOMS published in 1982 Proposed International Guidelines for Biomedical
Research Involving Human Subjects. The purpose of the Guidelines was to
indicate how the fundamental ethical principles that guide the conduct of biomedical
research involving human subjects, as set forth in the World Medical Association's
Declaration of Helsinki, could be applied effectively, particularly in developing
countries, taking into account culture, socioeconomic circumstances, national
laws, and executive and administrative arrangements.

The publication was distributed to ministries of health, medical research councils,
medical faculties, non-governmental organizations, research-based pharmaceutical
companies, other interested bodies and medical journals. Comments on the Guidelines
and suggestions for amendments were received from many sources. Also CIOMS carried
out a questionnaire survey, with due representation of developing countries
and all six WHO regions. The responses indicated that biomedical scientists
in many countries appreciated the ethical guidance the Guidelines provided,
particularly in assuring the validity of informed consent and otherwise protecting
the rights and welfare of research subjects; they suggested also various areas
for amendment and review.

In the years that followed, it became obvious that a number of developing countries
were finding the Guidelines helpful in setting up their own arrangements for
independent ethical review of proposed biomedical research projects but that
certain changes in emphasis were needed.

Also since 1982 there have been considerable advances in medical sciences and
biotechnology, and the potential of human biomedical research has continued
to expand. The AIDS epidemic, particularly the need to carry out vaccine and
drug trials, has raised ethical questions that were not foreseen when the Declaration
of Helsinki was formulated, or even only ten years ago when the CIOMS Guidelines
were issued. In some countries people at risk of HIV infection have claimed
a right to access to clinical research and to incompletely tested new treatments.
In some societies, the deliberate exclusion from research of women who are pregnant
of capable of becoming pregnant, to avoid risk to the fetus has begun to be
questioned on the grounds that it deprives such women of benefits and denies
them their right to decide for themselves whether to take part in research.
Similarly, the growth of geriatric medicine and geriatric pharmacology has created
pressure for the inclusion of elderly people in medical research for their own
benefit.

International and intercultural collaborative research has increased considerably
and involves developing countries, many of which have yet a very limited capacity
for independent review of research proposals

Submitted by either external sponsors and investigators or their own research
workers.

Finally, there is some concern about biomedical research involving human subjects
being regarded as a benefit to its subjects and to society, rather than only
as a source of risk to its subjects. Many people regard this claim with some
apprehension in case research will be undertaken or promoted without adequate
justification and secure safeguards of the rights and welfare of the research
subjects.

In all these circumstances it appeared timely to revise the 1982 Guidelines,
with a view to reaffirming in today's conditions their original purpose  the
protection of the rights and welfare of human subjects of biomedical research.

INTERNATIONAL DECLARATIONS AND GUIDELINES

The first international document on the ethics of research, the Nuremberg Code,
was promulgated in 1947 as a consequence of the trial of physicians who had
conducted atrocious experiments on unconsenting prisoners and detainees during
the second world war. The Code, designed to protect the integrity of the research
subject, sets out conditions for the ethical conduct of research involving human
subjects, emphasizing the human subject's "voluntary consent" to research.

To give the Universal Declaration of Human Rights, adopted by the United Nations
General Assembly in 1948, legal as weIl as moral force, the General Assembly
of the United Nations adopted in 1966 the International Covenant on Civil and
Political Rights, of which Article 7 states " No one shall be subjected to
torture or to cruel, inhuman or degrading treatment or punishment. In particular,
no one shall be subjected without his free consent to medical or scientific
experimentation. "

The Declaration of Helsinki, promulgated in 1964 by the World Medical Association,
is the fundamental document in the field of ethics in biomedical research and
has had considerable influence on the formulation of international, regional
and national legislation and codes of conduct. The Declaration, revised in Tokyo
in 1975, in Venice in 1983, and again in Hong Kong in 1989, is a comprehensive
international statement of the ethics of research involving human subjects.
It sets out ethical guidelines for physicians engaged in both clinical and non-
clinical biomedical research, and provides among its rules for informed consent
of subjects and ethical review of the research protocol. The Declaration of
Helsinki is appended (Annex 1).

The publication in 1982 of Proposed International Guidelines for Biomedical
Research Involving Human Subjects was a logical development of the Declaration
of Helsinki. As stated in the Introduction of that publication, the Guidelines
were intended to indicate how the ethical principles embodied in the Declaration
could be effectively applied in developing countries. The text explained the
application of established ethical principles to biomedical research involving
human subjects and drew attention to new ethical issues arising in the period
that preceded its publication. The present publication, International Ethical
Guidelines for Biomedical Research Involving Human Subjects, supersedes
the 1982 Proposed International Guidelines.

CIOMS and WHO have continued to work together to provide ethical guidance for
research involving human subjects. One important outcome of this cooperation has
been International Guidelines for Ethical Review of Epidemiological Studies,
published by CIOMS in 1991, intended to assist investigators and institutions
as weIl as regional and national authorities in setting and maintaining standards
for the ethical review of epidemiological studies.

GENERAL ETHICAL PRINCIPLES

All research involving human subjects should be conducted in accordance with
three basic ethical principles, namely respect for persons, beneficence and
justice. It is generally agreed that these principles, which in the abstract
have equal moral force, guide the conscientious preparation of proposals for
scientific studies. In varying circumstances they may be expressed differently
and given different moral weight, and their application may lead to different
decisions or courses of action. The present guidelines are directed at the application
of these principles to research involving human subjects.

a) respect for autonomy, which requires that those who are capable
of deliberation about their personal choices should be treated with respect
for their capacity for self-determination; and

b) protection of persons with impaired or diminished autonomy, which
requires that those who are dependent or vulnerable be afforded security
against harm or abuse.

Beneficence refers to the ethical obligation to maximize benefits and
to minimize harms and wrongs. This principle gives rise to norms requiring that
the risks of research be reasonable in the light of the expected benefits, that
the research design be sound, and that the investigators be competent both to
conduct the research and to safeguard the welfare of the research subjects.
Beneficence further proscribes the deliberate infliction of harm on persons;
this aspect of beneficence is sometimes expressed as a separate principle, non-maleficience
(do no harm).

Justice refers to the ethical obligation to treat each person in accordance
with what is morally right and proper, to give each person what is due to him
or her. In the ethics of research involving human subjects the principle refers
primarily to distributive justice, which requires the equitable distribution
of both the burdens and the benefits of participation in research. Differences
in distribution of burdens and benefits are justifiable only if they are based
on morally relevant distinctions between persons; one such distinction is vulnerability.
"Vulnerability" refers to a substantial incapacity to protect one's own interests
owing to such impediments as lack of capability to give informed consent, lack
of alternative means of obtaining medical care or other expensive necessities,
or being a junior or subordinate member of a hierarchical group. Accordingly,
special provisions must be made for the protection of the rights and welfare
of vulnerable persons.

PREAMBLE

The term "research" refers to a class of activities designed to develop or
contribute to generalizable knowledge. Generalizable knowledge consists of theories,
principles or relationships, or the accumulation of information on which they
are based, that can be corroborated by accepted scientific methods of observation
and inference. In the present context "research" includes both medical and behavioural
studies pertaining to human health. Usually "research" is modified by the adjective
"biomedical" to indicate that the reference is to health-related research.

Progress in medical care and disease prevention depends upon an understanding
of physiological and pathological processes or epidemiological findings, and
requires at some time research involving human subjects. The collection, analysis
and interpretation of information obtained from research involving human beings
contribute significantly to the improvement of human health.

Research involving human subjects includes that undertaken together with patient
care (clinical research) and that undertaken on patients or other subjects,
or with data pertaining to them, solely to contribute to generalizable knowledge
(non-clinical biomedical research). Research is defined as "clinical" if one
or more of its components is designed to be diagnostic, prophylactic or therapeutic
for the individual subject of the research. Invariably, in clinical research,
there are also components designed not to be diagnostic, prophylactic or therapeutic
for the subject; examples include the administration of placebos and the performance
of laboratory tests in addition to those required to serve the purposes of medical
care. Hence the term "clinical research" is used here rather than "therapeutic
research".

Research involving human subjects includes:

studies of a physiological, biochemical or pathological process, or of the
response to a specific intervention  whether physical, chemical or psychological-
in healthy subjects or patients;

controlled trials of diagnostic, preventive or therapeutic measures in larger
groups of persons, designed to demonstrate a specific generalizable response
to these measures against a background of individual biological variation

studies designed to determine the consequences for individuals and communities
of specific preventive or therapeutic measures; and

studies concerning human health-related behaviour in a variety of circumstances
and environments.

Research involving human subjects may employ either observation or physical,
chemical or psychological intervention; it may also either generate records
or make use of existing records containing biomedical or other information about
individuals who mayor may not be identifiable from the records or information.
The use of such records and the protection of the confidentiality of data obtained
from those records are discussed in International Guidelines for Ethical
Review of Epidemiological Studies (CIOMS, 1991).

Research involving human subjects includes also research in which environmental
factors are manipulated in a way that could affect incidentally-exposed individuals.
Research is defined in broad terms in order to embrace field studies of pathogenic
organisms and toxic chemicals under investigation for health-related purposes.

Research involving human subjects is to be distinguished from the practice
of medicine, public health and other forms of health care, which is designed
to contribute directly to the health of individuals or communities. Prospective
subjects may find it confusing when research and practice are to be conducted
simultaneously, as when research is designed to obtain new information about
the efficacy of a drug or other therapeutic, diagnostic or preventive modality.

Research involving human subjects should be carried out only by, or strictly
supervised by, suitably qualified and experienced investigators and in accordance
with a protocol that clearly states: the aim of the research; the reasons for
proposing that it involve human subjects; the nature and degree of any known
risks to the subjects; the sources from which it is proposed to recruit subjects;
and the means proposed for ensuring that subjects' consent will be adequately
informed and voluntary. The protocol should be scientifically and ethically
appraised by one or more suitably constituted review bodies, independent of
the investigators.

New vaccines and medicinal drugs, before being approved for general use, must
be tested on human subjects in clinical trials; such trials, which constitute
a substantial part of all research involving human subjects, are described in
Annex 2.

THE GUIDELINES

Informed Consent of Subjects

Guideline 1: Individual informed consent

For all biomedical research involving human subjects, the investigator must
obtain the informed consent of the prospective subject or, in the case of an
individual who is not capable of giving informed consent, the proxy consent
of a properly authorized representative.

Commentary on Guideline 1

General considerations. Informed consent is consent given by a competent
individual who has received the necessary information; who has adequately understood
the information; and who, after considering the information, has arrived at
a decision without having been subjected to coercion, undue influence or inducement,
or intimidation.

Informed consent is based on the principle that competent individuals are entitled
to choose freely whether to participate in research. Informed consent protects
the individual's freedom of choice and respects the individual's autonomy.

In itself, informed consent is an imperfect safeguard for the individual, and
it must always be complemented by independent ethical review of research proposals.
Moreover, many individuals, including young children, many adults with severe
mental or behavioural disorders, and many persons who are totally unfamiliar
with modern medical concepts, are limited in their capacity to give adequate
informed consent. Because their consent could imply passive and uncomprehending
participation, investigators must on no account presume that consent given by
such vulnerable individuals is valid, without the prior approval of an independent
ethical-review body. When an individual is incapable of making an informed decision
whether to participate in research, the investigator must obtain the proxy consent
of the individual's legal guardian or other duly authorized representative.

When the research design involves no more than minimal risk- that is, risk
that is no more likely and not greater than that attached to routine medical
or psychological examination -and it is not practicable to obtain informed consent
from each subject (for example, where the research involves only excerpting
data from subjects' records) the ethical review committee may waive some or
all of the elements of informed consent. Investigators should never initiate
research involving-human subjects without obtaining each subject's informed
consent, unless they

have received explicit approval to do so from an ethical review committee.

Guideline 2: Essential information for
prospective research subjects

Before requesting an individual's consent to participate in research, the
investigator must provide the individual with the following information, in
language that he or she is capable of understanding:

that each individual is invited to participate as a subject in research,
and the aims and methods of the research; -the expected duration of the subject's
participation; -the benefits that might reasonably be expected to result to
the subject or to others as an outcome of the research;

any foreseeable risks or discomfort to the subject, associated with participation
in the research;

any alternative procedures or courses of treatment that might be as advantageous
to the subject as the procedure or treatment being tested;

the extent to which confidentiality of records in which the subject is
identified will be maintained;

the extent of the investigator's responsibility , if any, to provide
medical services to the subject;

that therapy will be provided free of charge for specified types of research-related
injury;

whether the subject or the subject's family or dependants will be compensated
for disability or death resulting from such injury; and

that the individual is free to refuse to participate and will be free
to withdraw from the research at any time without penalty or loss of benefits
to which he or she would otherwise be entitled.

Commentary on Guideline 2

Process. Obtaining informed consent is a process that is begun when
initial contact is made with a prospective subject and continues throughout
the course of the study. By informing the subjects, by repetition and explanation,
by answering subjects' questions as they arise, and by assuring that each procedure
is understood by each subject, the research team not only elicits the informed
consent of subjects but also manifests deep respect for the dignity of the subjects.

Language. Informing the subject must not be simply a ritual recitation
of the contents of a form. Rather, the investigator must convey the information
in words that suit the individual's level of understanding.

The investigator must bear in mind that ability to understand the information
necessary to give informed consent depends on the individual's maturity, intelligence,
education and rationality.

Comprehension. The investigator must then ensure that the prospective
subject has adequately understood the information. This obligation is the more
serious as risk to the subject increases. Insome instances the investigator
might administer an oral or a written test to check whether the information
has been adequately understood.

Benefits. Inresearch designed to evaluate vaccines, drugs or other
products, subjects should be told whether and how the product will be made available
to them if it proves to be safe and effective. They should be told whether they
will have continuing access to the product between the end of their participation
in the research and the time of approval of the product for general distribution,
and whether they will receive it free of charge or will be expected to pay for
it.

Risks. In the case of complex research projects it may be neither feasible
nor desirable to inform prospective subjects fully about every possible risk.
However, they must be informed of all risks that a reasonable person would consider
material to making a decision about whether to participate. An investigator's
judgment about what risks are to be considered material should be reviewed and
approved by the ethical review committee (see Guideline 3). Subjects who desire
additional information should be afforded an opportunity to ask questions.

The investigator's responsibility for medical care. If the investigator
is a physician, the subject must be told clearly whether the investigator will
act only as an investigator or as both an investigator and a physician to the
subject. However, an investigator who agrees to act as physician- investigator
undertakes all of the legal and ethical responsibilities of the subject's primary-care
physician. Insuch a case, if the subject withdraws from the research
owing to complications related to the research or in the exercise of the right
to withdraw without loss of benefit, the physician has an obligation to continue
to provide medical care to the subject, or to see that the subject receives
the necessary care in the community or district health-care system, or to offer
assistance in finding another physician.

If the investigator is to act only as an investigator, the subject must be
advised to seek any necessary medical care, outside the context of the research.

Other considerations. For further details of the obligation to provide
economic compensation in the event of death or disability resulting from specified
types of research-related injury, see Guideline 13. For further discussion of
confidentiality, see Guideline 12.

Guideline 3: Obligations of investigators
regarding informed consent

The investigator has a duty to:

communicate to the prospective subject all the information necessary
for adequately informed consent;

give the prospective subject full opportunity and encourage- ment to
ask questions;

exclude the possibility of unjustified deception, undue influence and
intimidation;

seek consent only after the prospective subject has adequate knowledge
of the relevant facts and of the consequences of participation, and has had
sufficient opportunity to consider whether to participate;

as a general rule, obtain from each prospective subject a signed form
as evidence of informed consent; and

renew the informed consent of each subject if there are material changes
in the conditions or procedures of the research.

Commentary on Guideline 3

Necessary information. The standards for communicating information as
set forth in Guidelines 2 and 3 should be regarded as minimum. Other types of
information that should be conveyed include the reasons for selecting prospective
subjects (ordinarily because they either have certain diseases or have no apparent
disease) and certain features of the research design (for example, randomization,
double-blind, case-control), stated in language that the subjects can understand.
Additional types of information that should be conveyed in some circumstances
are suggested below in the commentaries on several other guidelines. In general
the standard for communicating information is that any and all information that
a reasonable person would consider material to reaching a decision about whether
to consent should be communicated. Investigators and ethical review committees
should determine together what should be communicated in connection with particular
studies.

Opportunity to ask questions. The investigator must be prepared to answer
all of the subject's questions relating to the proposed research. Any restriction
of the subject's ability to ask questions and receive answers before or during
the research undermines the validity of the informed consent.

Deception. Sometimes, to ensure valid research, subjects are deliberately
misled. In biomedical research, deception mostly takes the form of withholding
information about the purpose of procedures; for example, subjects in clinical
trials are of ten not told the purpose of tests performed to monitor their compliance
with the protocol, in case that if they knew their compliance was being monitored
they would modify their behaviour and thus invalidate the results. In most such
cases the prospective subjects are asked to consent to remain uninformed of
the purpose of some procedures until the research is completed; in other cases,
because a request for permission to withhold some information would jeopardize
the validity of the research, prospective subjects are not made aware that some
information has been withheld until the research is completed.

Telling lies to subjects is a tactic not commonly employed in biomedical research.
However, social and behavioural scientists may deliberately misinform subjects
to study their attitudes and behaviour; for example, scientists have pretended
to be patients to study the behaviour of health-care professionals and patients
in their natural settings.

Deception of the subject is not permissible in research projects that carry
more than minimal risk of harm to the subject. When deception is indispensable
to the methods of an experiment, the investigator must demonstrate to an ethical
review committee that no other research method would suffice; that significant
advances could result from the research; and that nothing has been withheld
that, if divulged, would cause a reasonable person to refuse to participate.
The ethical review committee with the investigator should determine whether
and how deceived subjects should be informed of the deception upon completion
of the research. Such informing, commonly called "debriefing", ordinarily entails
explaining the reasons for the deception. A subject who disapproves of having
been deceived is ordinarily offered an opportunity to refuse to allow the investigator
to use information obtained from studying the subject.

Undue influence. The investigator should seek to exclude any undue
influence on the subject. However, the borderline between justifiable persuasion
and undue influence is imprecise. The investigator should not give the prospective
subject any unjustifiable assurances about the benefits, risks or inconveniences
of the research. An example of undue influence would be to induce a close relative
or a community leader to influence a prospective subject's decision or to threaten
to withhold health services. See also Guideline 4.

Intimidation. Intimidation in any form invalidates informed consent.
Prospective subjects who are patients often depend upon the investigator for
medical care, and the investigator has a certain credibility in their eyes.
If the research protocol has a therapeutic component, the investigator's influence
over them may be considerable. They may fear, for example, that refusal to participate
would damage their relationship with the investigator. The investigator must
assure prospective subjects that their decision on whether to participate will
not affect the therapeutic relationship or any other benefits to which they
are entitled.

Documentation of consent. Consent may be indicated in a number of ways.
The subject may imply consent by his or her voluntary actions, express consent
orally, or sign a consent form. As a general rule, the subject should sign a
consent form, or, in the ca se of incompetence, a legal guardian or other duly
authorized representative should do so. The ethical review committee may approve
the waiving of the requirement of a signed consent form if the research carries
no more than minimal risk and if the procedures to be used are only those for
which signed consent forms are not customarily required outside the research
context. Such waivers may also be approved when existence of a signed consent
form would be an unjustified threat to the subjects' confidentiality. In some
cases, particularly when the information is complicated, it is advisable to
give subjects information sheets to retain; these may resemble consent forms
in all respects except that subjects are not required to sign them.

Continuing consent. The initial consent should be renewed when material
changes occur in the conditions or the procedures of the research. For example,
new information may have come to light, either from the study or from outside
the study, about the risks or benefits of therapies being tested or about alternatives
to the therapies. Subjects should be given such information. In many clinical
trials, data are not disclosed to subjects and investigators until the study
is concluded. This is ethically acceptable if the data are monitored by a committee
responsible for data and safety monitoring (see Guideline 14, page 40) and an
ethical review committee has approved their non-disclosure.

Guideline 4: Inducement to participate

Subjects may be paid for inconvenience and time spent, and should be reimbursed
for expenses incurred, in connection with their participation in research; they
may also receive free medicalservices. However, the payments should
not be so large or the medical services so extensive as to induce prospective
subjects to consent to participate in the research against their better judgment
("undue inducement"). All payments, reimbursements and medical services to be
provided to research subjects should be approved by an ethical review committee.

Commentary on Guideline 4

Acceptable recompense. Research subjects may have their transport and
other expenses reimbursed and receive a modest allowance for inconvenience due
to their participation in the research. Also, investigators may provide them
with medical services and the use of facilities, and perform procedures and
tests free of charge, provided these are done in connection with the research.

Unacceptable recompense. Payments in money or in kind to research subjects
should not be so large as to persuade them to take undue risks or volunteer
against their better judgment. Payments or rewards that undermine a person's
capacity to exercise free choice invalidate consent. It may be difficult to
distinguish between suitable recompense and undue influence to participate in
research. An unemployed person or a student may view promised recompense differently
from an employed person. Someone without access to medical care may be unduly
influenced to participate in research simply to receive such care. Therefore,
monetary and in-kind recompense must be evaluated in the light of the traditions
of the particular culture and population in which they are offered, to determine
whether they constitute undue influence. The ethical review committee will ordinarily
be the best judge of what constitutes reasonable material recompense in particular
circumstances.

Incompetent persons. Incompetent persons may be vulnerable to exploitation
for financial gain by guardians. A guardian asked to give proxy consent on behalf
of an incompetent person should be offered no remuneration except a refund of
out-of-pocket expenses.

Withdrawal from study. When a subject withdraws from research for reasons
related to the study, or is withdrawn on health grounds, the investigator should
pay the subject as if full participation had taken place. When a subject withdraws
for any other reason, the investigator should pay in proportion to the amount
of participation. An investigator who must remove a subject from the study for
wilful noncompliance is entitled to withhold part or all of the payment.

Guideline 5: Research involving children

Before undertaking research involving children, the investigator must ensure
that:

children will not be involved in research that might equally well be
carried out with adults;

the purpose of the research is to obtain knowledge relevant to the health
needs of children;

a parent or legal guardian of each child has given proxy consent;

the consent of each child has been obtained to the extent of the child's
capabilities;

the child's refusal to participate in research must always be respected
unless according to the research protocol the child would receive therapy
for which there is no medically- acceptable alternative;

the risk presented by interventions not intended to benefit the individual
child-subject is low and commensurate with the importance of the knowledge
to be gained; and

interventions that are intended to provide therapeutic benefit are likely
to be at least as advantageous to the individual child-subject as any available
alternative.

Commentary on Guideline 5

Justification of the involvement of children. The participation of children
is indispensable for research into diseases of childhood and conditions to which
children are particularly susceptible. The aims of the research should be relevant
to the health needs of children.

Consent of the chi/d. The willing cooperation of the child should be
sought, after the child has been informed to the extent that the child's maturity
and intelligence permit. The age at which a child becomes legally competent
to give consent differs substantially from one jurisdiction to another; in some
countries the "age of consent" established in their different provinces, states
or other political subdivisions varies considerably. Often children who have
not yet reached the legally established age of consent can understand the implications
of informed consent and go through the necessary procedures; they can therefore
knowingly agree to serve as research subjects. Such knowing agreement is insufficient
to permit participation in research unless it is supplemented by the proxy consent
of a parent, legal guardian or other duly authorized representative.

Older children who are capable of informed consent should be selected before
younger children or infants, unless there are important scientific reasons related
to age for involving younger children first. An

objection by a child to taking part in research should always be respected
even if the parent gives proxy consent, unless according to the research protocol
the child would receive therapy for which there is no medically- acceptable
alternative; in such a case parents or guardians may properly be authorized
to override the objections of the child, particularly if the child is very young
or immature.

Proxy consent of a parent or guardian. The investigator must obtain
the proxy consent of the parent or guardian in accordance with local laws or
established procedures. It may be assumed that children over the age of 13 years
are usually capable of giving informed consent, but their consent must be complemented
by the proxy consent of a parent or guardian, unless this is not required by
local law.

Observation of research by parent. A parent or guardian who gives proxy
consent for a child to participate in research should be given the opportunity
to observe the research as it proceeds, so as to be able to withdraw the child
from the research if the parent or guardian decides it is in the child's best
interests to do so.

Psychological and medical support. Research involving children should
be conducted in settings in which the child and the parent can obtain adequate
medical and psychological support. As an additional protection for children,
an investigator may, when possible, obtain the advice of a child's family physician
or other health-care provider on matters concerning the child's involvement
in the research.

Justification of risks. Interventions intended to provide direct diagnostic,
therapeutic or preventive benefit for the individual child-subject must be justified
by the expectation that they will be at least as advantageous to the individual
child-subject, considering both risks and benefits, as any available alternative.
Risks are to be justified in relation to anticipated benefits to the child.

The risk of interventions that are not intended to be of direct benefit to
the child-subject must be justified in relation to anticipated benefits to society
(generalizable knowledge ). In general, the risk from such interventions should
be minimal  that is, no more likely and not greater than the risk attached
to routine medical or psychological examination of such children. When an ethical
review committee is persuaded that the object of the research is sufficiently
important, slight increases above minimal risk may be permitted.

Guideline 6: Research involving persons with
mental or behavioural disorders

Before undertaking research involving individuals who by reason of mental
or behavioural disorders are not capable of giving adequately informed consent,
the investigator must ensure that:

such persons will not be subjects of research that might equally well
be carried out on persons in full possession of their mental faculties;

the purpose of the research is to obtain knowledge relevant to the particular
health needs of persons with mental or behavioural disorders;

the consent of each subject has been obtained to the extent of that subject's
capabilities, and a prospective subject's refusal to participate in non-clinical
research is always respected;

in the case of incompetent subjects, informed consent is obtained from
the legal guardian or other duly authorized person;

the degree of risk attached to interventions that are not intended to
benefit the individual subject is low and commensurate with the importance
of the knowledge to be gained; and

interventions that are intended to provide therapeutic benefit are likely
to be at least as advantageous to the individual subject as any alternative.

Commentary on Guideline 6

General considerations. Although the two populations differ in many
respects, the ethical considerations discussed earlier in the case of children
apply by and large to persons who are unable to give adequately informed consent
by reason of mental or behavioural disorders. They should never be subjects
of research that might equally well be carried out on adults in full possession
of their mental faculties, but they are clearly the only subjects suitable for
a large part of research into the origins and treatment of certain severe mental
or behavioural disorders.

Consent of the individual. People with mental or behavioural disorders
may not be capable of giving adequately informed consent. The willing cooperation
of such prospective subjects should be sought to the extent that their mental
state permits, and any objection on their part to taking part in any non-clinical
research should always be respected. When a' investigational intervention is
intended to be of therapeutic benefit to subject, the subject's objection should
be respected unless there is no reasonable medical alternative and local law
permits overriding the objection.

Proxy consent of the guardian. The Declaration of Helsinki states "In
case of legal incompetence, informed consent should be obtained from the legal
guardian in accordance with national legislation. Where physical or mental incapacity
makes it impossible to obtain informed consent... permission from the responsible
relative replaces that of the subject in accordance with national legislation"
(Article I. 11).

The agreement of an immediate family member  whether spouse, parent, adult
offspring or sibling  should be sought, but is sometimes of doubtful value,
especially as families sometimes regard persons with mental or behavioural disorders
as an unwelcome burden. In the case of an individual who has been committed
to an institution by a court order, it may be necessary to seek legal authorization
for involving the person in research.

Serious illness in persons who are unable to give adequately informed consent
because of mental or behavioural disorders. Such persons who have, or are
at risk of, serious illnesses such as HIV infection, cancer or hepatitis should
not be deprived of the possible benefits of investigational drugs, vaccines
or devices that show promise of therapeutic or preventive benefit, particularly
when no superior or equivalent therapy or prevention is available. Their entitlement
to access to such therapy or prevention is justified ethically on the same grounds
as is such entitlement for other vulnerable groups (see Guideline 10). Persons
who are unable to give adequately informed consent by reason of mental or behavioural
disorders are, in general, not suitable subjects for formal clinical trials
except those designed to be responsive to their particular health needs. Direct
HIV infection of the brain may result in mental impairment; in the case of patients
with such impairment, formal clinical trials of drugs, vaccines and other interventions
designed to treat or prevent the impairment may be approved by an ethical review
committee.

Anticipated incapacity to give informed consent. When it can be reasonably
predicted that a competent person will lose the capacity to make valid decisions
about medical care, as in the case of early manifestations of cognitive impairment
due to HIV infection or Alzheimer's disease, such a person may be asked to designate
the conditions, if any, in which he or she would consent to becoming a research
subject while unable to communicate, and to designate a person who will consent
on his or her behalf in accordance with the subject's previously expressed wishes.

Guideline 7: Research involving prisoners

Prisoners with serious illness or at risk of serious illness should not
arbitrarily be denied access to investigational drugs, vaccines or other agents
that show promise of therapeutic or preventive benefit.

Commentary on Guideline 7

General considerations. Guideline 7 is not intended as an endorsement
of involving prisoners as research subjects. The involvement of volunteer prisoners
in biomedical research is permitted in very few countries, and even in those
is controversial.

Advocates of allowing prisoners to participate in research argue that they
are particularly suitable in that they are living in a standard physical and
psychological environment; that unlike fully-employed or mobile populations
they have time to participate in long-term experiments; and that they regard
such participation as relief from the tedium of prison life, evidence of their
social worth, and a chance to earn a small income.

Opponents claim that the consent of prisoners cannot be valid in that it is
influenced by the hope of rewards and other expectations, such as earlier parole.

Although none of the international declarations bars prisoners from serving
as subjects of biomedical research, the contradictory though persuasive arguments
preclude an internationally agreed recommendation. However, where the practice
is permitted, there should be provision for the independent monitoring of the
research projects.

Prisoners and serious illness. Prisoners suffering from or at risk of
serious illnesses such as HIV infection, cancer or hepatitis should not be deprived
of the possible benefits of investigational drugs, vaccines or devices, particularly
when no superior or equivalent products are available. Their entitlement to
access to such therapy and prevention is justified ethically on the same grounds
as is that of other vulnerable groups (see Guideline 10). However, as no diseases
afflict prisoners only, one cannot sustain arguments analogous to those supporting
the suitability of children and of persons with mental or behavioural disorders
as subjects in formal clinical trials.

Before undertaking research involving subjects in underdeveloped communities,
whether in developed or developing countries, the investigator must ensure that:

persons in underdeveloped communities will not ordinarily be involved
in research that could be carried out reasonably well in developed communities;

the research is responsive to the health needs and the priorities of
the community in which it is to be carried out;

every effort will be made to secure the ethical imperative that the consent
of individual subjects be informed; and

the proposals for the research have been reviewed and approved by an
ethical review committee that has among its members or consultants persons
who are thoroughly familiar with the customs and traditions of the community.

Commentary on Guideline 8

General considerations. Diseases that rarely or never occur in economically
developed countries or communities exact a heavy toll of illness, disability
or death in some communities that are socially and economically at risk of being
exploited for research purposes, Research into the prevention and treatment
of such diseases is needed and, in general, must be carried out in large part
in the countries and communities at risk.

The ethical implications of research involving human subjects are identical
in principle wherever the work is undertaken; they relate to respect for the
dignity of each individual subject as well as to respect for communities, and
protection of the rights and welfare of human subjects. Assessment of inherent
risks is a pre-eminent concern. However, a number of subsidiary considerations
apply particularly to research undertaken in underdeveloped communities of either
developing or developed countries, by investigators and sponsors from developed
countries or from developed institutions of developing countries.

Individuals and families in such communities are liable to exploitation for
various reasons. Some of them may be relatively incapable of informed consent
because they are illiterate, unfamiliar with the concepts of medicine held by
the investigators, or living in communities in which the procedures typical
of informed-consent discussions are unfamiliar or alien to the ethos of the
community. Certain investigators may wish to take advantage of the lack in most
developing countries of well-developed regulations or ethical review committees,
which could have the effect of delaying access to research subjects; others
may find it less expensive to conduct in developing countries research designed
to develop drugs and other products for the markets of developed countries.

Guideline 8 is written on the presumption that research in developing countries
or underdeveloped communities will generally be conducted by investigators and
sponsored by agencies from developed countries or from developed communities
of developing countries. Such investigators or sponsors may encounter practices
that would be considered immoral in their own countries. This should be anticipated
and the range of acceptable responses by the sponsors and investigators should
be detailed in the protocol submitted to an ethical committee for review and
approval.

Investigators must respect the ethical standards of their own countries and
the cultural expectations of the societies in which research is undertaken,
unless this implies a violation of a transcending moral role. Investigators
risk harming their reputation by pursuing work that host countries find acceptable
but their own countries find offensive. Similarly, they may transgress the cultural
values of the host countries by uncritically conforming to the expectations
of their own.

Nature of the research. To guard against exploitation of individuals
and families in socially and economically exploitable communities, sponsors
and investigators who wish to conduct in such communities research that could
be carried out reasonably well in developed communities must satisfy their national
or local ethical review committees, and in the case of externally sponsored
research the appropriate ethical review committee in the host country, that
the research would not be exploitative. The reason for choosing an underdeveloped
community should be made explicit.

The research conducted in underdeveloped communities should be responsive to
the health needs and priorities of those communities. It should not exhaust
resources which the community usually devotes to the health care of its members.
If any product is to be developed, such as a new therapeutic agent, clear understanding
should be reached among investigators, sponsors, representatives of the collaborating
countries, and community leaders about what the community is to expect and what
can or cannot be provided during and at the close of the research. Such understanding
must be reached before the research is begun, to ensure that the research is
truly responsive to the priorities of the community.

As a general role, the sponsoring agency should ensure that, at the completion
of successful testing, any product developed will be made reasonably available
to inhabitants of the underdeveloped community in which the research was carried
out; exceptions to this general requirement should be justified, and agreed
to by all concerned parties before the research is begun.

Phase I drug studies and Phase I and II vaccine studies (Annex 2) should be
conducted only in developed communities of the country of the sponsor. In general,
Phase III vaccine trials and Phase II and III drug trials should be conducted
simultaneously in the host community and the sponsoring country; they may be
omitted in the sponsoring country on condition only that the drug or vaccine
is designed to treat or prevent a disease or other condition that rarely or
never occurs in the sponsoring country.

Informed consent. All reasonable efforts should be made to obtain the
informed consent of each prospective subject according to the standards specified
in Guidelines 1 to 3, to ensure that the rights of prospective subjects are
respected. For example, when because of communication difficulties investigators
cannot make prospective subjects sufficiently aware of the implications of participation
to give adequately informed consent, the decision of each prospective subject
on whether to consent should be elicited through a reliable intermediary such
as a trusted community leader. In some cases other mechanisms, approved by an
ethical review committee, may be more suitable. However consent is obtained,
all prospective subjects must be clearly told that their participation is entirely
voluntary, and that they are free to refuse to participate or to withdraw their
participation at any time without loss of any entitlement. The investigator
is required to ensure that each prospective subject is clearly told everything
that would be conveyed if the study were to be conducted in a developed community
and, further, to ensure that earnest attempts are made to enable the prospective
subject to understand this information; otherwise, assurance of freedom to refuse
or withdraw from participation would be meaningless.

All plans to use the above standard for informing, providing assistance with
understanding, and assuring freedom to refuse or withdraw must be approved by
an ethical review committee and supplemented with other means of assuring that
the rights of prospective subjects are respected.

Ethical review. The ability to judge the ethical acceptability of various
aspects of a research proposal requires a thorough understanding of a community's
customs and traditions. The ethical review committee must have as either members
or consultants persons with such understanding, so that the committee may evaluate
proposed means of obtaining informed consent and otherwise respecting the rights
of prospective subjects. Such persons should be able, for example, to identify
appropriate members of the community to serve as intermediaries between investigators
and subjects, to decide whether material benefits or inducements may be regarded
as appropriate in the light of a community's gift-exchange traditions, and to
provide safeguards for data and personal information that subjects consider
to be private or sensitive.

HIV/AIDS considerations. HIV infection and AIDS are endemic in many
of the world's countries and communities, both developed and developing. Some
features of HIV/AIDS justify the involvement of people from underdeveloped communities
in epidemiological research relevant to the HIV/AIDS pandemic as well as in
research designed to test candidate drugs and vaccines for the treatment and
prevention of HIV infection and AIDS. These include, but are not limited to,
evidence that modes of transmission of the infection, and the natural history
of the disease, may differ substantially among communities. Moreover, strains
of HIV are different in various regions of the world, and the current scientific
understanding is that different strains may respond differently to vaccines
or drugs. If research were conducted only in developed countries and communities,
developing countries could be deprived of many of the benefits of such research.
Therefore, participation in HIV/AIDS research of inhabitants of appropriately
selected underdeveloped communities should be encouraged, provided their rights
and welfare are adequately safeguarded as set forth in Guideline 8.

Guideline 9: Informed consent in epidemiological
studies

For several types of epidemiological research individual informed consent
is either impracticable or inadvisable. In such cases the ethical review committee
should determine whether it is ethically acceptable to proceed without individual
informed consent and whether the investigator's plans to protect the safety
and respect the privacy of research subjects and to maintain the confidentiality
of the data are adequate.

Commentary on Guideline 9

General considerations. For epidemiological studies it is normal for
investigators to secure the agreement and cooperation of the national or local
authority responsible for public health in the population to be studied. In
the case of a community in which collective decision-making is customary it
is also advisable to seek the agreement of the community, usually through its
chosen representatives.

Informed consent. Epidemiological studies that require the examination
of documents, such as medical records, or of anonymous "leftover" samples of
blood, urine, saliva or tissue specimens may be conducted without the consent
of the individuals concerned, as long as their right to confidentiality is assured
by the study methods.

When the focus of a study is an entire community rather than individual human
subjects  for example, to test the use of an additive in a community's water
supply, or a new health care procedure or method, or a new method of control
of disease vectors such as mosquitoes or rats  individual consent or an individual's
refusal to be exposed to the intervention would be meaningless unless the individual
were willing to leave the community. However, individuals may refuse to submit
to such procedures as questionnaires or blood tests designed to obtain data
for evaluating the intervention.

When epidemiological studies entail personal contact between investigators
and individual subjects, the general requirements for informed consent are directly
applicable. When they involve individuals primarily as members of population
groups, it may be acceptable not to obtain the informed consent of each individual.
In the case of population groups with social structures, common customs, and
an acknowledged leadership, the investigator will need to secure the cooperation
and obtain the agreement of the group's leadership. In the case of groups defined
solely in demographic or statistical terms, with neither leaders nor representatives,
the investigator must satisfy an ethical review committee that the safety of
the research subjects and the confidentiality of the data will be strictly safeguarded.

Consent is not required for the use of publicly available information, but
the investigator should know that countries and communities differ with regard
to what information about individuals is considered public. Investigators who
use such information should avoid disclosure of personally sensitive information.

In the case of studies of certain forms of social behaviour, an ethical review
committee may determine that it would be inadvisable to seek individual informed
consent because to do so would frustrate the purpose of a study; for example,
prospective subjects on being informed of the behaviour to be studied would
change the behaviour. The review committee must be satisfied that there will
be adequate safeguards of confidentiality and that the importance of the objectives
of the research is in proportion to the risks to the subjects.

Investigators who propose to carry out epidemiological studies should consult
International Guidelines for Ethical Review of Epidemiological Studies (CIOMS,
1991).

Selection of Research Subjects

Guideline 10: Equitable distribution of burdens and benefits

Individuals or communities to be invited to be subjects of research should
be selected in such a way that the burdens and benefits of the research will
be equitably distributed. Special justification is required for inviting vulnerable
individuals and, if they are selected, the means of protecting their rights
and welfare must be particularly strictly applied.

Commentary on Guideline 10

General considerations. In general, the equitable distribution of the
burdens and the benefits of participation in research raises no serious problems
when the intended subjects do not include vulnerable

individuals or communities. Occasionally, when research is designed to evaluate
therapeutic agents widely perceived to offer substantial advantages over those
generally available, it may be appropriate to publicize widely the opportunity
to participate in the research or to establish outreach programmes for individuals
or groups who have no ready access to information about research programmes.

Equitable distribution of the burdens and benefits of research participation
is generally more difficult when the intended subjects include vulnerable individuals
or groups. Classes of individuals traditionally considered vulnerable are those
with limited capacity or freedom to consent. They are the subject of specific
guidelines in this publication and include children, persons who because of
mental or behavioural disorders are incapable of giving informed consent, and
prisoners. Ethical justification of their involvement usually requires that
investigators satisfy ethical review committees that:

the research could not be carried out reasonably well with less vulnerable
subjects;

the research is intended to obtain knowledge that will lead to improved
diagnosis, prevention or treatment of diseases or other health problems characteristic
of or unique to the vulnerable class, either the actual subjects or other
similarly situated members of the vulnerable class;

research subjects and other members of the vulnerable class from which subjects
are recruited will ordinarily be assured reasonable access to any diagnostic,
preventive or therapeutic products that will become available as a consequence
of the research;

the risks attached to research that is not intended to benefit individual
subjects will be minimal, unless an ethical review committee authorizes a
slight increase above minimal risk (see Guideline 5); and

when the prospective subjects are either incompetent or otherwise substantially
unable to give informed consent, their agreement will be supplemented by the
proxy consent of their legal guardians or other duly authorized representatives.

Other vulnerable social groups. The quality of the consent of prospective
subjects who are junior or subordinate members of a hierarchical group requires
careful consideration, as their agreement to volunteer may be unduly influenced
by the expectation, whether justified or not, of preferential treatment or by
fear of disapproval or retaliation if they refuse. Examples of such groups are
medical and nursing students, subordinate hospital and laboratory personnel,
employees of pharmaceutical companies, and members of the armed forces or police.

Because they work in close proximity to investigators or disciplinary superiors,
they tend to be called upon more often than others to serve as research subjects,
and this could result in inequitable distribution of the burdens and benefits
of research.

Other groups or classes may also be considered vulnerable. They include residents
of nursing homes, people receiving welfare benefits or social assistance and
other poor people and the unemployed, patients in emergency rooms, some ethnic
and racial minority groups, homeless persons, nomads, refugees, and patients
with incurable disease. To the extent that these and other classes of people
have attributes resembling those of classes identified as vulnerable, the need
for special protection of their rights and welfare should be considered.

Persons with HIV infection or at risk of contracting HIV infection. Persons
in this category are not vulnerable in the sense of having limited capacity
to consent. However, certain features of HIV infection and of the AIDS pandemic
have prompted reconsideration of some aspects of the ethics of research involving
human subjects; as a result, various countries have developed policies and practices
designed to be responsive to the special problems presented by HIV infection;
some of these problems are discussed in the following paragraphs. Although this
commentary concerns problems associated with HIV infection, the basic principles
apply equally to problems associated with other more or less similar conditions.

Drogs and other therapies that have not yet been licensed for general availability
because studies designed to establish their safety and efficacy remain to be
completed are sometimes made available to persons with HIV infection. This is
compatible with the Declaration of Helsinki, Article II.1, which states "...the
physician must be free to use a new diagnostic or therapeutic measure, if in
his or her judgment it offers hope of saving life, reestablishing health or
alleviating suffering."

Drugs and other therapies that are made available, because they show promise
of therapeutic benefit, to persons not considered vulnerable should be made
equally available to members of vulnerable populations, particularly when no
superior or equivalent approaches to therapy are available; children, pregnant
or nursing women, persons with mental disorders who are not capable of giving
informed consent, and prisoners are entitled to equal access to the benefits
of such investigational agents unless there is good reason, such as a medical
contraindication, not to afford such access.

When women take investigational drugs for HIV infection, special precautions
are often needed. Women who are not pregnant when they begin to take such drugs
should be counselled about reliable contraception. In developed countries, nursing
mothers who ask to be treated with investigational drugs for HIV infection should
be advised that they must discontinue breast-feeding while taking such drugs,
unless there is clear evidence that the drug does not appear in milk. In each
case in which an investigational drug is administered to a pregnant or nursing
woman, there should be careful monitoring and reporting of the effects, if any,
on the fetus or child.

Although it is generally required that research be conducted on less vulnerable
populations before involving more vulnerable populations, some exceptions are
justified. Ingeneral, children are not suitable subjects for Phase I
drug trials or for Phase I or II vaccine trials, but in some cases such trials
may be permissible after clinical trials in adults have shown some degree of
therapeutic effect. For example, a Phase II vaccine trial seeking evidence of
immunogenicity in infants may be justified in the case of a vaccine that has
shown evidence of preventing or slowing progression from asymptomatic HIV infection
to disease in adults. Additional examples are provided in the commentaries on
Guidelines 6 and 8.

The life-threatening and infectious nature of HIV/AIDS does not justify any
suspension of the rights of research subjects to informed consent, voluntary
participation in or withdrawal from the study, or protection of confidentiality.
Inthe case of research protocols that provide for diagnostic tests for
HIVinfection, the procedures for obtaining informed consent should be
supplemented by counselling in which each subject is informed about AIDS and
HIV infection, advised to avoid risky behaviour, and advised of the risk of
social discrimination against individuals who are thought to be HIV-infected
or at risk of such infection. Inthe case of patients with HIV disease
or persons becoming aware of being HIV-infected, research teams should provide
them with necessary services or refer them for follow-up.

Participation in drug and vaccine trials in the field of HIV infection and
AIDS may impose on the research subjects significant associated risks of social
discrimination or harm; such risks merit consideration equal to that given to
the adverse medical consequences of the drugs and vaccines. Efforts must be
made to reduce their likelihood and severity. For example, participants in vaccine
trials must be enabled to demonstrate that their HIVseropositivity is
due to their having been vaccinated rather than to natural infection. This may
be accomplished by providing subjects with documents attesting to their participation
in vaccine trials, or by maintaining a confidential register of trial participants,
from which information can be made available to outside agencies at a participant's
request.

Guideline 11: Selection of pregnant or nursing
(breastfeeding) women as research subjects

Pregnant or nursing women should in no circumstances be the subjects of
non-clinical research unless the research carries no more than minimal risk
to the fetus or nursing infant and the object of the research is to obtain new
knowledge about pregnancy or lactation. As a general rule, pregnant or nursing
women should not be subjects of any clinical trials except such trials as are
designed to protect or advance the health of pregnant or nursing women or fetuses
or nursing infants, and for which women who are not pregnant or nursing would
not be suitable subjects.

Commentary on Guideline 11

General considerations. In general, pregnant and nursing women are not
suitable subjects of formal clinical trials other than those designed to respond
to the health needs of such women or their fetuses or nursing infants. Examples
of such trials would be a trial designed to test the safety and efficacy of
a drug for reducing perinatal transmission of HIV infection from mother to child,
a trial of a device for detecting fetal abnormalities, or trials of therapies
for conditions associated with or aggravated by pregnancy, such as nausea and
vomiting, hypertension or diabetes. The justification for their participation
in such clinical trials would be that they should not be deprived arbitrarily
of the opportunity to benefit from investigational drugs, vaccines or other
agents that promise therapeutic or preventive benefit. In all cases risks to
women subjects, fetuses and infants should be minimized, as far as sound research
design permits.

A woman may decide to discontinue nursing to become eligible to participate
in clinical research, but this is not to be encouraged, particularly in developing
countries, where cessation of breast-feeding may be harmful to the nursing child
and also increase the risk of another pregnancy.

Selection of women as research subjects Women in most societies have
been discriminated against with regard to their involvement in research. Women
who are biologically capable of becoming pregnant have been customarily excluded
from formal clinical trials of drugs, vaccines, and devices owing to concern
about undetermined risks to the fetus. Consequently, relatively little is known
about the safety and efficacy or most drugs, vaccines, or devices for such w
omen, and this lack of knowledge can be dangerous. For example, thalidomide
caused much more extensive damage than it would have if its first administration
to such women had been in the context of a formal, carefully-monitored clinical
trial.

A general policy of excluding from such clinical trials w omen biologically
capable of becoming pregnant is unjust in that it deprives women as a class
of persons of the benefits of the new knowledge derived from the trials. Further,
it is an affront to their right of self-determination. The exclusion of such
w omen can be justified only on such grounds as evidence or suspicion that a
particular drug or vaccine is mutagenic or teratogenic. Nevertheless, although
women of child-bearing age should be given the opportunity to participate in
research, they should be helped to understand that the research could include
risks to the fetus.

Premenopausal women have also been excluded from participation in many research
activities, including non-clinical studies, that do not entail administration
of drugs or vaccines, in case the physiological changes associated with various
phases of the menstrual cycle would complicate interpretation of research data.
Consequently, much less is known of women's than of men's normal physiological
processes. This, too, is unjust in that it deprives women as a class of persons
of the benefits of such knowledge.

Informed consent. Obtaining the informed consent of women, including
those who are pregnant or nursing, usually presents no special problems. In
some cultures, however, women's rights to exercise self-determination and thus
give valid informed consent are not acknowledged.Insuch cases,
women should not normally be involved in research for which societies that recognize
these rights require informed consent. Nevertheless, women who have serious
illnesses or who are at risk of developing such illnesses should not be deprived
of opportunities to receive investigational therapies when there are no better
alternatives, even though they may not consent for themselves. Efforts must
be made to let such women know of these opportunities and to invite them to
decide whether they wish to accept the investigational therapy, even though
the formal consent must be obtained from another person, usually a man. Such
invitations may best be extended by women who understand the culture sufficiently
well to discern whether prospective recipients of investigational therapies
genuinely wish to accept or reject the therapy.

Research related to termination of pregnancy. No recommendation is made
regarding the acceptability of research relating to the termination of pregnancy,
or undertaken in anticipation of termination of pregnancy. The acceptability
of such research depends on religious belief, cultural traditions and national
legislation.

Confidentiality of Data

Guideline 12: Safeguarding confidentiality

The investigator must establish secure safeguards of the confidentiality
of research data. Subjects should be told of the limits to the investigators'
ability to safeguard confidentiality and of the anticipated consequences of
breaches of confidentiality.

Commentary on Guideline 12

General considerations. The Declaration of Helsinki, Article 1.6, states:
"The right of the research subject to safeguard his or her integrity must always
be respected. Every precaution should be taken to respect the privacy of the
subject and to minimize the impact of the study on the subject's physical and
mental integrity and on the personality of the subject." The customary approach
to showing respect for privacy is by obtaining prior informed consent to releases
of research data and minimizing the possibility of a breach of confidentiality.
If the requirement of individual informed consent is to be waived by an ethical
review committee, alternative measures should be taken. Such measures are discussed
in International Guidelines for Ethical Review of Epidemiological Studies
(CIOMS, 1991).

Confidentiality between physician and patient. Patients in therapeutic
relationships with their physicians have the right to expect that all information
will be held in strict confidence and disclosed only to those who need, or have
a legal right to, the information, such as nurses and technicians, to treat
the patients. A treating physician should not disclose any identifying data
about patients to an investigator unless the patients have first given their
consent to such disclosure.

Physicians and other health care professionals record the details of their
observations and interventions in medical and other records. Epidemiologists
and other investigators of ten make use of such records. In studies of medical
records it is usually impracticable to obtain the informed consent of each identifiable
patient. Accordingly, an ethical review committee may waive the requirement
for informed consent. In institutions in which records may be used for research
purposes without the informed consent of identifiable patients, it is advisable
to notify patients generally of such practices; notification is usually by means
of a statement in patient-information brochures.

In the case of research limited to subjects' medical records, access must be
approved by an ethical review committee and must be supervised by a person who
is fully aware of the confidentiality requirements.

Confidentiality between investigator and subject. Research relating
to individuals and groups may involve the collection and storage of data that,
if disclosed to third parties, could cause harm or distress. Investigators should
arrange to protect the confidentiality of such data by, for example, omitting
information that might lead to the identification of individual subjects, limiting
access to the data, or other means.

Prospective subjects should be informed of limits to the investigators' ability
to ensure strict confidentiality and of the foreseeable adverse social consequences
of limitations or breaches of confidentiality. In some cases investigators are
required to communicate data from records to a national drug registration authority
or to an industrial sponsor of the research. Some jurisdictions require the
reporting of, for instance, certain communicable diseases to public health authorities
or evidence of child abuse or neglect to appropriate agencies. These and similar
limits to the ability to maintain confidentiality should be anticipated and
disclosed to prospective subjects.

Compensation of Research Subjects for Accidental
Injury

Guideline 13: Right of subjects to compensation

Research subjects who suffer physical injury as a result of their participation
are entitled to such financial or other assistance as would compensate them
equitably for any temporary or permanent impairment or disability. In the case
of death, their dependants are entitled to material compensation. The right
to compensation may not be waived.

Commentary on Guideline 13

Accidental injury. Accidental injury due to procedures performed exclusively
to accomplish the purposes of research rarely results in death or in permanent
or temporary impairment or disability. Death, impairment or disability is much
more likely to result from investigational diagnostic, preventive or therapeutic
interventions. In general, however, death or serious injury is less likely to
result from investigational therapies administered in the context of properly
designed, conducted and sanctioned studies than from similar standard therapies
in routine medical practice. Usually, human research subjects are in exceptionally
favourable circumstances in that they are under close and continuing observation
by qualified investigators alert to detecting the earliest signs of untoward
reactions. Such favourable conditions are less likely in medical practice.

Equitable compensation. Compensation is owed to subjects who sustain
significant physical injury from procedures performed solely to accomplish the
purposes of research. Justice requires that every subject of biomedical research
be automatically entitled to fair compensation for any such injury. Compensation
is generally not owed to research

subjects who suffer expected or foreseen adverse reactions from investigational
therapies or other procedures performed to diagnose or prevent disease. Such
reactions are not different in kind from those that occur in medical practice.

When, as in the early stages of drug testing, it is unclear whether a procedure
is performed primarily for research or for therapeutic purposes, the ethical
review committee should determine in advance the injuries for which subjects
will be compensated and those for which they will not; prospective subjects
should be informed of the review committee's decisions, as part of the informed
consent process.

Subjects should not be required to waive their rights to compensation or to
show negligence or lack of a reasonable degree of skill on the part of the investigator
in order to claim compensation. The informed consent process or form should
contain no words that would absolve an investigator from responsibility in the
case of accidental injury, or that would imply that subjects would waive their
legal rights, including the right to seek compensation for injury.

In some societies the right to compensation for accidental injury is not acknowledged.
Therefore, when giving their informed consent to participate, research subjects
should be told whether there is provision for compensation in case of physical
injury, and the circumstances in which they or their dependants would receive
it.

Obligation of the sponsor to pay .The sponsor, whether a pharmaceutical
company, a government, or an institution, should agree, before the research
begins, to provide compensation for any physical injury for which subjects are
entitled to compensation. Sponsors are advised to obtain adequate insurance
against risks to cover compensation, independent of proof of fault.

All proposals to conduct research involving human subjects must be submitted
for review and approval to one or more independent ethical and scientific review
committees. The investigator must obtain such approval of the proposal to conduct
research before the research is begun.

Commentary on Guideline 14

General considerations. The provisions for review of research involving
human subjects are influenced by political institutions, the organization of
medical practice and research, and the degree of autonomy accorded to medical
investigators. Whatever the circumstances, however, society has a dual responsibility
to ensure that:

all drugs, devices and vaccines under investigation in human subjects meet
adequate standards of safety; and

the provisions of the Declaration of Helsinki are applied in all biomedical
research involving human subjects.

Assessment of safety. Authority to assess the safety and quality of
medicines and vaccines intended for use in humans is most effectively vested
in a multidisciplinary advisory committee. In many cases such committees will
function best if they operate at the national level; in other instances they
are most effective at regional or local level. Clinicians, clinical pharmacologists,
pharmacologists, microbiologists, epidemiologists, statisticians and other experts
have important contributions to offer to such assessment. Many countries lack
the resources to assess technical data independently according to procedures
and standards now required in the more developed countries. Improvement in this
respect depends, in the short term, on more efficient exchange of information
internationally.

Ethical review committees. Scientific review and ethical review cannot
be clearly separated: scientifically unsound research on human subjects is ipso
facto unethical in that it may expose subjects to risk or inconvenience
to no purpose. Normally, therefore, ethical review committees consider both
the scientific and the ethical aspects of proposed research.

Scientific review. The Declaration of Helsinki, Article 1.1, states
that "biomedical research involving human subjects must conform to generally
accepted scientific principles and should be based on adequately performed laboratory
and animal experimentation and on a thorough knowledge of the scientific literature."

Committees competent to review and approve scientific aspects of clinical trials
must be multidisciplinary, much like those specified earlier for assessment
of safety. In many cases such committees operate most effectively at the national
level. A national scientific review committee offers several advantages over
local committees. First, consolidating the necessary expertise in one group
allows members to deepen their knowledge in the field, thereby improving the
quality and utility of the review. Second, a national committee's awareness
of all proposals for research in the country facilitates the performance of
another essential function, the selection of those protocols most likely to
achieve the nation's health research objectives.

If an ethical review committee considers a research proposal scientifically
sound, or verifies that a competent expert body has found it so, it will then
consider whether any known or possible risks to the subjects are justified by
the expected benefits (and whether the methods of carrying out the research
will minimize harm and maximize benefit) and, if so, whether the procedures
proposed for obtaining informed consent are satisfactory and those proposed
for selection of subjects are equitable.

Risks and benefits. The Declaration of Helsinki forbids the imposition
of unwarranted risks on human research subjects. Article 1.4 requires that "the
importance of the objective is in proportion to the inherent risk to the subject."
The need for means of preventing or treating HIV infection or AIDS, for example,
is obvious justification of research aimed at developing such treatment or prevention.
However, it may not be possible to justify clinical testing of all investigational
substances. Clinical testing must be preceded by sufficient laboratory experiments,
including, when appropriate, animal testing, to demonstrate a reasonable probability
of success without undue risk. Such preliminary testing is implied by the Declaration
of Helsinki, Article 1.7, which requires ting research involving human subjects
unless "the hazards involved are believed to be predictable", and by Article
1.5, which requires that clinical testing "be preceded by careful assessment
of predictable risks in comparison with foreseeable benefits to the subject
others."

Ideeally, when benefits are intended for society but not for the subject, the
subjects should be individuals who are fully capable of informed consent and
who understand and accept the risks. Thus, unless there is specially strong
justification, Phases I and II of vaccine testing and Phase I of drug testing
should not involve subjects with limited capacity to consent or who are otherwise
vulnerable. The requirement of the Declaration of Helsinki, Article III.2, that
"subjects should be volunteers  either healthy persons or patients for whom
the experimental design is not related to the patient's illness" is not to be
disregarded lightly.

In Phases II and III of drug testing and Phase III of vaccine testing, when
benefits are intended for the subjects and they are reasonably likely to be
realized, it is permissible to involve members of vulnerable groups and persons
with limited capacity to consent. However, as required by the Declaration of
Helsinki, Article II.3, "every patient including those of a control group,
if any  should be assured of the best proven diagnostic and therapeutic method."
Therefore, if there is already an approved and accepted drug for the condition
that a candidate drug is designed to treat, placebo for controls usually cannot
be justified.

Ethical justification to begin a randomized clinical trial also meets the requirements
of Article II.3. The therapies (or other interventions) to be compared must
be regarded as equally advantageous to the prospective subjects: there should
be no scientific evidence to establish the superiority of one over another.
Moreover, no other intervention must be known to be superior to those being
compared in the clinical trial, unless eligibility to participate is limited
to persons who have been unsucessfully treated with the other superior intervention
or to persons who are aware of the other intervention and its superiority and
have chosen not to accept it.

For each randomized clinical trial there should be a data and safety monitoring
committee, responsible for monitoring the data obtained in the course of a study
and for making recommendations to the sponsors and investigators about modifying
or terminating the study, or about amending the informed-consent process or
form. Such recommendations are made in response to the committee's detection
of adverse events of which the nature, frequency or magnitude had not been anticipated
by the investigators or sponsors as they planned the study, or of evidence that
one of the therapies or preventive measures being tested in the clinical trial
is superior to another. During the planning stage of a clinical trial, stopping-rules
should be established to guide the data and safety monitoring committee in determining
when it should recommend termination of the study.

National or local review. Review committees may be created under the
aegis of national or local health administrations, national medical research
councils or other nationally-representative bodies. In a highly centralized
administration, a national review committee may be constituted for both the
scientific and the ethical review of research protocols. In countries where
medical research is not centrally directed, protocols are more effectively and
conveniently reviewed from the ethical standpoint at a local or regional level.
The competence of a local committee may be confined exclusively to a single
research institution or may extend to all human-subject biomedical research
undertaken within a defined geographical area. The basic responsibilities of
local ethical review committees are twofold:

to verify that all proposed interventions, and particularly the administration
of drugs and vaccines or use of medical devices under development, have been
assessed by a competent expert body as acceptably safe to be undertaken in
human subjects; and

to ensure that all other ethical concerns arising from a protocol are satisfactorily
resolved both in principle and in practice.

Committee membership. Local review committees should be so composed
as to be able to provide complete and adequate review of the research activities
referred to them. They should include physicians, scientists and other professionals,
such as nurses, lawyers, ethicists and clergy, as well as lay persons qualified
to represent the cultural and moral values of the community. The membership
should include both men and women. Committees that often review research directed
at specific diseases or impairments, such as AIDS or paraplegia, should consider
the advantages of including as members or consultants patients with such diseases
or impairments. Similarly, committees that review research involving such vulnerable
groups as children, students, aged persons or employees should consider the
advantages of including representatives of, or advocates for, such groups. Membership
should be rotated periodically with the aim of blending the advantages of experience
with those of openness to cultural and scientific evolution. Independence from
the investigators and avoidance of conflict of interest are maintained by excluding
from the assessment of a proposal any member with a direct interest in the proposal.

Need for particularly stringent review requirements. The requirements
of review committees should be particularly stringent in the case of proposed
research involving children, pregnant and nursing w omen, persons with mental
or behavioural disorders, communities unfamiliar with modem clinical concepts,
and other vulnerable social groups, and in the case of invasive non-clinical
research. In considering such proposals the review committee should be especially
attentive in determining that selection of research subjects is both equitable
(designed to distribute fairly the burdens and benefits of research) and likely
to minimize risk to subjects.

Multicentre research. Some research projects are designed to be conducted
in a number of sites in different communities or countries. Generally, to ensure
that the results will be valid, the study must be conducted in an identical
way at each of the different sites. Such studies include multicentre clinical
trials, evaluation of health service programmes, and various kinds of epidemiological
research. In such studies local ethical review committees must either accept
or reject the protocol in its entirety; they must not impose requirements to
change doses of drugs, to change inclusion or exclusion criteria, or to make
other similar modifications. In some such studies, scientific and ethical review
may be facilitated by agreement among institutions to accept the results of
review by a single review committee, who se members would include representatives
of ethical review committees at each of the places in which the research is
to be conducted.

Sanctions. Ethical review committees generally have no authority to
impose sanctions on investigators who violate ethical standards in the conduct
of research involving human subjects. However, they should be required to report
to institutional or governmental authorities any serious or continuing noncompliance
with ethical standards as they are reflected in protocols that they have approved.
Failure to submit a protocol to the committee should be considered a violation
of ethical standards.

Sanctions imposed by institutional, governmental, professional or other authorities
possessing disciplinary power should be employed as a last resort. Preferred
methods of control include cultivation of an atmosphere of mutual trust, and
education and support to promote in investigators and in sponsors the capacity
for ethical conduct of research.

Should sanctions become necessary, they should be directed at the noncompliant
investigators or sponsors. They may include fines or suspension of eligibility
to receive research funding, to use investigational therapies, or to practise
medicine. Refusal to publish the results of research conducted unethically,
as prescribed in the Declaration of Helsinki, Article 1.8, may be considered,
as may refusal to accept unethically obtained data submitted in support of an
application for drug registration. However, these sanctions deprive of benefit
not only the errant investigator or sponsor but also that segment of society
intended to benefit from the research; such possible consequences merit careful
consideration.

Publications of reports of the results of research involving human subjects
should include, when appropriate, a statement that the research was conducted
in accordance with these guidelines. Departures, if any, from these guidelines
should be explained and justified in the report submitted for publication.

Information to be provided by investigators. Whatever the procedure
adopted for ethical review, such review should be based on a detailed protocol
comprising:

a clear statement of the research objectives, having regard to the present
state of knowledge, and a justification for undertaking the investigation
in human subjects;

a precise description of all proposed interventions, including intended
dosages of drugs and planned duration of treatment;

a description of plans to withdraw or withhold standard therapies in the
course of the research;

a description of the plans for statistical analysis of the study, which
includes a calculation of the statistical power of the study, specifies the
criteria for terminating the study, and demonstrates that the proper number
of subjects will be recruited;

the criteria determining admission and withdrawal of individual subjects,
including full details of the procedure for seeking and obtaining informed
consent;

an account of any economic or other inducements to participate, such as
offers of cash payments, gifts, or free services or facilities, and of any
financial obligations assumed by the subjects, such as payment for medical
services; and

for research carrying more than minimal risk of physical injury, an account
of plans, if any, to provide medical therapy for such injury and to provide
compensation for research-related disability or death.

Information should also be included to establish:

the safety of each proposed intervention and of any drug or vaccine
to be tested, including the results of relevant laboratory and animal
research;

the anticipated benefits and the risks of participation;

the means proposed to obtain individual informed consent or, when
a prospective subject is not capable of informed consent, satisfactory
assurance that proxy consent will be obtained from a duly authorized
person and that the rights and welfare of each subject will be adequately
protected;

the identification of the organization that is sponsoring the research
and a detailed account of the sponsor's financial commitments to the
research institution, investigators, research subjects and, when appropriate,
the community;

plans to inform subjects about harms and benefits during the study,
and of the results of the study at its conclusion;

an explanation of who will be involved in the research, their age,
sex and circumstances, and, if any classes are excluded, the justification
for the exclusion;

justification for involving as research subjects persons with limited
capacity to consent or members of vulnerable social groups;

evidence that the investigator is qualified and experienced and is
assured of adequate facilities for the safe and efficient conduct of
the research;

provisions that will be made for protecting the confidentiality of
data; and,

the nature of any other ethical considerations involved, together
with an indication that the principles of the Declaration of Helsinki
will be implemented.

Externally Sponsored Research

Guideline 15: Obligations of sponsoring and host countries

Externally sponsored research entails two ethical obligations:

An external sponsoring agency should submit the research protocol to
ethical and scientific review according to the standards of the country of
the sponsoring agency, and the ethical standards applied should be no less
exacting than they would be in the case of research carried out in that country.

After scientific and ethical approval in the country of the sponsoring
agency, the appropriate authorities of the host country, including a national
or local ethical review committee or its equivalent, should satisfy themselves
that the proposed research meets their own ethical requirements.

Commentary on Guideline 15

Definition. The term "externally sponsored research" refers to research
undertaken in a host country but sponsored, financed, and sometimes wholly or
partly carried out by an external international or national

agency, with the collaboration or agreement of the appropriate authorities,
institutions and personnel of the host country.

Ethical and scientific review. Committees in both the country of the
sponsoring agency and the host country have responsibility for conducting both
scientific and ethical review, as well as the authority to withhold approval
of research proposals that fail to meet their scientific or ethical standards.
Special responsibilites may be assigned to review committees in the two countries
when a sponsor or investigator in a developed country proposes to carry out
research in a developing country. When the external sponsor is an international
agency the research protocol must be reviewed according to its own independent
ethical review procedures and standards.

Committees in the external sponsoring country or international agency have
a special responsibility to determine whether the scientific methods are sound
and suitable for the aims of the research, whether the drugs, vaccines or devices
to be studied meet adequate standards of safety, whether there is sound justification
for conducting the research in the host country rather than in the country of
the external sponsoring agency, and that the proposed research does not in principle
violate the ethical standards of the external sponsoring country or international
organization.

Committees in the host country have the special responsibility to determine
whether the goals of the research are responsive to the health needs and priorities
of the host country. Moreover, because of their better understanding of the
culture in which the research is proposed to be carried out, they have special
responsibility for assuring the equitable selection of subjects and the acceptability
of plans to obtain informed consent, to respect privacy, to maintain confidentiality,
and to offer benefits that will not be considered excessive inducements to consent.

In short, ethical review in the external sponsoring country may be limited
to ensuring compliance with broadly stated ethical standards, on the understanding
that ethical review committees in the host country will have greater competence
in reviewing the detailed plans for compliance in view of their better understanding
of the cultural and moral values of the population in which the research is
proposed to be conducted.

Research designed to develop therapeutic, diagnostic or preventive products.
When externally sponsored research is initiated and financed by an industrial
sponsor such as a pharmaceutical company, it is in the interest of the host
country to require that the research proposal be submitted with the comments
of a responsible authority of the initiating country, such as a health administration,
research council, or academy of medicine or science.

Externally sponsored research designed to develop a therapeutic, diagnostic
or preventive product must be responsive to the health needs of the host country.
It should be conducted only in host countries in

which the disease or other condition for which the product is indicated is
an important problem. As a general rule, the sponsoring agency should agree
in advance of the research that any product developed through such research
will be made reasonably available to the inhabitants of the host community or
country at the completion of successful testing. Exceptions to this general
requirement should be justified and agreed to all concerned parties before the
research begins. Consideration should be given to whether the sponsoring agency
should agree to maintain in the host country, after the research has been completed,
health services and facilities established for purposes of the study.

Obligations of external sponsors. An important secondary objective of
externally sponsored collaborative research is to help develop the host countrys
capacity to carry out similar research projects independently, including their
ethical review. Accordingly, external sponsors are expected to employ and, if
necessary, train local individuals to function as investigators, research assistants,
or data managers or in other similar capacities. When indicated, sponsors should
also provide facilities and personnel to make necessary health-care services
available to the population from which research subjects are recruited. Although
sponsors are not obliged to provide health-care facilities or personnel beyond
that which is necessary for the conduct of the research, to do so is morally
praiseworthy. However, sponsors have an obligation to ensure that subjects who
suffer injury as a consequence of research interventions obtain medical treatment
free of charge, and that compensation is provided for death or disability occurring
as a consequence of such injury (see Guideline 13 for a statement of the scope
and limits of such obligations). Also, sponsors and investigators should refer
for health care services subjects who are found to have diseases unrelated to
the research, and should advise prospective subjects who are rejected as research
subjects because they do not meet health criteria for admission to the investigation
to seek medical care. Sponsors are expected to ensure that research subjects
and the communities for which they are recruited are not made worse off as a
result of the research (apart from justifiable risks of research interventions)
 for example, by the diversion of scarce local resources to research activities.
Sponsors may disclose to the proper authorities in the host country information
that relates to the health of the country or community, discovered in the course
of a study.

External sponsors are expected to provide, as necessary, reasonable amounts
of financial, educational and other assistance to enable the host country
to develop its own capacity for independent ethical review of research
proposals and to form independent and competent scientific and ethical
review committees. To avoid conflict of interest, and to assure the independence
of committees, such assistance should not be provided directly to the
committees; rather funds should be made available to the host-country
government or to the host research-institution.

Obligations of sponsors will vary with the circumstances of particular studies
and the needs of host countries. The sponsors obligations in particular
studies should be clarified before research is begun. The research protocol
should specify what, if any, resources, facilities, assistance and other
goods or services will be made available during and after the research,
to the community from which the subjects are drawn and to the host country
.The details of these arrangements should be agreed by the sponsor, officials
of the host country, other interested parties, and, when relevant, the
community from which subjects are to be drawn. The ethical review committee
in the host country should determine whether any or all of these details
should be made a part of the consent process.

Annex 1

WORLD MEDICAL ASSOCIATION DECLARATION

OF HELSINKI

Recommendations guiding physicians
in biomedical research involving human subjectsAdopted by the 18th World Medical Assembly
Helsinki, Finland, June 1964
and amended by the
29th World Medical Assembly
Tokyo, Japan, October 1975

INTRODUCTION
It is the mission of the physician to safeguard the health of the people. His
or her knowledge and conscience are dedicated to the fulfillment of this mission.

The Declaration of Geneva of the World Medical Association binds the physician
with the words, "The health of my patient will be my first consideration," and
the International Code of Medical Ethics declares that "A physician shall
act only in the patient's interest when providing medical care which might have
the effect of weakening the physical and mental condition of the patient."

The purpose of biomedical research involving human subjects must be to improve
diagnostic, therapeutic and prophylactic procedures and the understanding of
the aetiology and pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic procedures
involve hazards. This applies especially to biomedical research.

Medical progress is based on research which ultimately must rest in part on
experimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be recognized
between medical research in which the aim is essentially diagnostic or therapeutic
for a patient, and medical research, the essential object of which is purely
scientific and without implying direct diagnostic or therapeutic value to the
person subjected to the research. Special caution must be exercised in the conduct
of research which may affect the environment, and the welfare of animals used
for research must be respected.

Because it is essential that the results of laboratory experiments be applied
to human beings to further scientific knowledge and to help suffering humanity,
the World Medical Association has prepared the following recommendations as
a guide to every physician in biomedical research involving human subjects.
They should be kept under review in the future. It must be stressed that the
standards as drafted are only a guide to physicians all over the world. Physicians
are not relieved from criminal, civil and ethical responsibilities under the
laws of their own countries.

I. BASIC PRINCIPLES

Biomedical research involving human subjects must conform to generally accepted
scientific principles and should be based on adequately performed laboratory
and animal experimentation and a thorough knowledge of the scientific literature.

The design and performance of each experimental procedure involving human
subjects should be clearly formulated in an experimental protocol which should
be transmitted for consideration, comment and guidance to a specially appointed
committee independent of the investigator and the sponsor, provided that this
independent committee is in conformity with the laws and regulations of the
country in which the research experiment is performed.

Biomedical research involving human subjects should be conducted only by
scientifically qualified persons and under the supervision of a clinically
competent medical person. The responsibility for the human subject must always
rest with a medically qualified person and never rest on the subject of the
research, even though the subject has given his or her consent.

Biomedical research involving human subjects cannot legitimately be carried
out unless the importance of the objective is in proportion to the inherent
risk to the subject.

Every biomedical research project involving human subjects should be preceded
by careful assessment of predictable risks in comparison with foreseeable
benefits to the subject or to others. Concern for the interests of the subject
must always prevail over the interests of science and society.

The right of the research subject to safeguard his or her integrity must
always be respected. Every precaution should be taken to respect the privacy
of the subject and to minimize the impact of the study on the subject's physical
and mental integrity and on the personality of the subject.

Physicians should abstain from engaging in research projects involving
human subjects unless they are satisfied that the hazards involved are
believed to be predictable. Physicians should cease any investigation
if the hazards are found to outweigh the potential benefits.

In publication of the results of his or her research, the physician is obliged
to preserve the accuracy of the results. Reports of experimentation not in
accordance with the principles laid down in this Declaration should not be
accepted for publication.

In any research on human beings, each potential subject must be adequately
informed of the aims, methods, anticipated benefits and potential hazards
of the study and the discomfort it may entail. He or she should be informed
that he or she is at liberty to abstain from participation in the study and
that he or she is free to withdraw his or her consent to participation at
any time. The physician should then obtain the subject's freely-given informed
consent, preferably in writing.

When obtaining informed consent for the research project the physician should
be particularly cautious if the subject is in a dependent relationship to
him or her or may consent under duress. In that case the informed consent
should be obtained by a physician who is not engaged in the investigation
and who is completely independent of this official relationship.

In case of legal incompetence, informed consent should be obtained from
the legal guardian in accordance with national legislation. Where physical
or mental incapacity makes it impossible to obtain informed consent, or when
the subject is a minor, permission from the responsible relative replaces
that of the subject in accordance with national legislation.
Whenever the minor child is in fact able to give a consent, the minor's consent
must be obtained in addition to the consent of the minor's legal guardian.

The research protocol should always contain a statement of the ethical considerations
involved and should indicate that the principles enunciated in the present
Declaration are complied with.

II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE
(Clinical research)

In the treatment of the sick person, the physician must be free to use a
new diagnostic and therapeutic measure, if in his or her judgement it offers
hope of saving life, reestablishing health or alleviating suffering.

The potential benefits, hazards and discomfort of a new method should be
weighed against the advantages of the best current diagnostic and therapeutic
methods.

In any medical study, every patient  including those of a control
group, if any  should be assured of the best proven diagnostic and
therapeutic method.

The refusal of the patient to participate in a study must never interfere
with the physician-patient relationship.

If the physician considers it essential not to obtain informed consent,
the specific reasons for this proposal should be stated in the experimental
protocol for transmission to the independent committee (1, 2).

The physician can combine medical research with professional care, the objective
being the acquisition of new medical knowledge, only to the extent that medical
research is justified by its potential diagnostic or therapeutic value for
the patient.

III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS

(Non-clinical biomedical research)

In the purely scientific application of medical research carried out on
a human being, it is the duty of the physician to remain the protector of
the life and health of that person on whom biomedical research is being carried
out.

The subjects should be volunteers  either healthy persons or patients for
whom the experimental design is not related to the patient's illness.

The investigator or the investigating team should discontinue the research
if in his/her or their judgement it may, if continued, be harmful to the individual.

In research on man, the interest of science and society should never take
precedence over considerations related wellbeing of the subject.

Annex 2

THE PHASES OF CLINICAL TRIALS OF VACCINES AND DRUGS

Vaccine development

Phase I refers to the first introduction of a candidate vaccine into
a human population for initial determination of its safety and biological effects,
including immunogenicity. This phase may include studies of dose and route of
administration, and usually involves fewer than 100 volunteers.

Phase II refers to the initial trials examining effectiveness in a limited
number of volunteers (usually between 200 and 500); the focus of this phase
is immunogenicity.

Phase III trials are intended for a more complete assessment of safety
and effectiveness in the prevention of disease, involving a larger number of
volunteers in a multicentre adequately controlled study.

Drug development

Phase I refers to the first introduction of a drug into humans. Normal
volunteer subjects are usually studied to determine levels of drugs at which
toxicity is observed. Such studies are followed by dose-ranging studies in patients
for safety and, in some cases, early evidence of effectiveness.

Phase II investigation consists of controlled clinical trials designed
to demonstrate effectiveness and relative safety. Normally, these are performed
on a limited number of closely monitored patients.

Phase III trials are performed after a reasonable probability of effectiveness
of a drug has been established and are intended to gather additional evidence
of effectiveness for specific indications and more precise definition of drug-related
adverse effects. This phase includes both controlled and uncontrolled studies.

Phase IV trials are conducted after the national drug registration authority
has approved a drug for distribution or marketing. These trials may include
research designed to explore a specific pharmacological effect, to establish
the incidence of adverse reactions, or to determine the effects of long-term
administration of a drug. Phase IV trials may also be designed to evaluate a
drug in a population not studied adequately in the premarketing phases (such
as children or the elderly) or to establish a new clinical indication for a
drug. Such research is to be distinguished from marketing research, sales promotion
studies, and routine postmarketing surveillance for adverse drug reactions in
that these

In general, Phase I drug trials and Phase I and Phase II vaccine trials should
be conducted according to the articles of the Declaration of Helsinki that refer
to non-clinical research. However, some exceptions can be justified. For example,
it is customary and ethically justifiable to conduct Phase I studies of highly
toxic chemotherapies of cancer in patients with cancer, rather than in normal
volunteers as prescribed in the Declaration of Helsinki, Article III.2. Similarly
be ethically it may be ethically justifiable to involve HIV-seropositive individuals
as subjects in Phase II trials of candidate vaccines.

Phase II and Phase III drug trials should be conducted according to the articles
of the Declaration of Helsinki that refer to "medical research, combined with
professional care (clinical research)". However, the Declaration does not to
provide for controlled clinical trials. Rather, it assures the freedom of the
physician "to use a new diagnostic and therapeutic measure, if in his or her
judgment it offers hope of saving life reestablishing health or alleviating
suffering" (Article II.1 ). Also in regard to Phase II and Phase III drug trials
there are customary and ethically justified exceptions to the requirements of
the Declaration of Helsinki. A placebo given to a control group, for example,
cannot be justified by its "potential diagnostic or therapeutic value for the
patient", as Article II.6 prescribes. Many other interventions and procedures
characteristic of late-phase drug development have no possible diagnostic or
therapeutic value for the patients and thus must be justified on other grounds;
usually such justification consists of a reasonable expectation that they carry
little or no risk and that t contribute materially to the achievement of the
goals of the research.

Phase III trials of vaccines do not use "a new diagnostic and therapeutic measure"
that offers "hope of saving life, reestablishing health or alleviating suffering"
(clinical research). Yet administration of the vaccine is intended to be a benefit
to the subject rather than the purely scientific application of medical research
carried out on a being" (non-clinical biomedical research). Thus, Phase III
vaccine-trials do not conform to either of the categories defined in the Declaration
of Helsinki.

APPENDIX I

MEMBERS OF THE STEERING COMMITTEE

ABDUSSALAM, M.
Former Chairman, WHO Advisory Committee
for Health Research for the Eastern Mediterranean
c/o Bundesgesundheitsamt
Berlin, Germany